Metabolism and excretion are two of the most important processes involved in terminating the action of a drug. The objective of the project is to provide useful insights into the metabolism and excretion of drugs by the liver and at the same time elucidate the mechanisms involved in each of the various processes. We have developed a method of segmented retrograde intrabiliary injection (SRII) to administer drugs up the biliary tree of the rat. With this procedure we have shown that there exists a transport system for uptake of glucose from bile, that certain bile acids can increase the permeability of the canalicular epithelium, that dehydrocholate blocks transport of morphine glucuronide on the canalicular rather than sinusoidal side of the hepatocyte and that SKF 525A causes sequestration of morphine glucuronide in the liver, an effect that is not related to inhibition of drug metabolism. The proposed research enlarges upon the site of action of inhibition of transport processes, site of action of agents that alter drug metabolism, discovery of basic transport systems as for amino acids nd some unusual modes of action such as permeability changes in the liver. By using the isolated in situ perfused rat liver, additional parameters of volume of distribuion and transit parameters will be determined. The importance of this work is that new innovative approaches to studying liver function, hepatoxic agents and drug transport and metabolism processe are proposed. Ultimately these findings may relate to practical problems such as the hepatotoxic action of estrogens, what happens to drugs in the biliary tree in such procedures as endoscopic retrograde cholangiopancreatography, sites of action of hepatoactive agents and regurgitation of bile in extrahepatic obstruction.